Molecular Mechanisms of Sigma Receptor 1-Mediated Neuroprotection

项目摘要： 本提案的一般目的是向主要研究者（PI）提供 成为一个成功和独立的愿景所需的经验和技能 研究员我的长期目标是发展一个独立的研究计划， 对青光眼的治疗方法的研究。青光眼是一种与年龄相关的眼病， 导致视神经内视网膜神经节细胞（RGC）死亡的神经病 神经。在本申请中，我们提出测试新靶点的配体， 分子伴侣蛋白sigma受体1（<$R1），可以保护RGCs免于死亡 在昏迷压力的条件下。几种青光眼模型都暗示 肿瘤坏死因子（TNF）是引起青光眼中RGC死亡的应激源。我们将 使用体外和体内模型系统来测试假设，即R1通过以下方式保护RGC： 抑制视网膜神经胶质细胞释放TNF？，并通过改变 RGC到TNF？我们将使用最近发现的啮齿动物模型来诱导增加 眼内压和敲除小鼠技术来验证我们的假设。 将实现以下三个目标： 1)使用以下方法检验<$R1配体调节神经胶质炎症反应的假设： 体外模型系统 2)测试假设，即<$R1激活改变了TNF <$介导的信号传导的平衡 在RGC中生存。 3)检验以下假设：<$R1激活改变了胶质细胞和神经元对眼刺激的反应。 高血压和<$R1配体将抑制神经胶质活化并保护免受RGC 在青光眼的体内模型中死亡。

Project Summary: The general purpose of this proposal is to provide the principle investigator (PI) with the experience and skills necessary to become a successful and independent vision researcher. My long-term goal is to develop an independent research program directed toward discovery of treatments for glaucoma. Glaucoma is an age-related optic neuropathy that results in the death of retinal ganglion cells (RGCs) within the optic nerve. In this application, we propose to test whether ligands for a novel target, the molecular chaperone protein sigma receptor 1(¿R1), can protect RGCs from death under conditions of glaucomatous stress. Several models of glaucoma have implicated tumor necrosis factor (TNF¿) as a stressor that causes RGC death in glaucoma. We will use in vitro and in vivo model systems to test the hypothesis that ¿R1 protects RGCs by suppressing retinal glial cell release of TNF¿ and by altering the signaling response of RGCs to TNF¿. We will use a recently discovered rodent model for inducing increased intraocular pressure and knockout mouse technology to test our hypothesis.The following three aims will be addressed: 1) Test the hypothesis that ¿R1 ligands modulate glial inflammatory responses using in vitro model systems. 2) Test the hypothesis that ¿R1 activation shifts the balance of TNF¿ mediated signaling towards survival within RGCs. 3) Test the hypothesis that ¿R1 activation alters glial and neuronal responses to ocular hypertension and that ¿R1 ligand will suppress glial activation and protect against RGC death in an in vivo model of glaucoma.